SK139994A3 - Taxane derivatives, their preparation and compositions containing same - Google Patents

Abstract

Novel taxane derivatives of formula (I), their preparation and pharmaceutical compositions containing same. In general formula (I), Ar is an aryl radical, R1 is a hydrogen atom or an acetyl radical or a radical according to formula (II) (wherein R1 and R2 denote hydrogen, alkyl or together form a heterocycle, n is equal to 2 or 3), R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl. The novel products of general formula (I) have outstanding tumour prevention activity.

Description

Novel taxane derivatives, processes for their preparation and pharmaceutical compositions containing them

Technical field

The invention relates to novel taxane derivatives, to a process for their preparation and to pharmaceutical compositions containing them.

SUMMARY OF THE INVENTION

The present invention relates to novel taxane derivatives of the formula I

in which

Ar represents an aryl group,

R represents a hydrogen atom or an acetyl group or a group of formula II

II

N- (CK ₂ ) n -NH-C (II)

in which

R 2 and R ₂ , which are the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms or R and R 2 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated a heterocycle optionally containing a further heteroatom selected from the group consisting of nitrogen, optionally substituted with C 1-4 alkyl or benzyl, oxygen and sulfur, n is 2 or 3, and

R represents a straight or branched (C 1 -C 8) alkyl group, (C 3 -C 8) alkenyl, (C 3 -C 8) alkynyl, (C 3 -C 6) cycloalkyl, (C 4 -C 6) cycloalkenyl or bicycloalkyl up to 10 carbon atoms optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxy, C1-4 alkyloxy, dialkylamino wherein each alkyl moiety contains 1 to 4 carbon atoms; 4 carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted at the 4-position with C 1-4 alkyl or phenylalkyl, in which the alkyl radical contains 1 to 4 carbon atoms, cycloalkyl containing 3 to C 6 -C 6 cycloalkenyl, phenyl, cyano, carboxyl or alkoxycarbonyl in which the alkyl radical contains 1 to 4 carbon atoms, or phenyl optionally substituted by one or more substituents selected a halogen atom, a C 1 -C 4 alkyl group and a C 2 -C 4 alkyloxy group, or a saturated or unsaturated 5 or 6 membered nitrogen heterocyclyl group optionally substituted by one or more alkyl groups containing C 1-4 alkyl, wherein the cycloalkyl, cycloalkenyl or bicycloalkyl group may be optionally substituted by one or more C 1-4 alkyl groups.

Ar is preferably phenyl or alpha or beta-naphthyl optionally substituted by one or more substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom), alkyl group, alkenyl group, alkynyl group, aryl group, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, the alkyl and other radicals of the other groups having 1 to 4 carbon atoms, alkenyl and alkynyl groups containing of 3 to 8 carbon atoms and aryl groups are phenyl or alpha or beta-naphthyl.

EP-A-0 253 738 discloses docetaxel (Taxotere ^R ) and Chem.Abstr., 107, 211532r (1987) discloses paclitaxel (Taxol ^R ) and its epimer at the 7-position having equivalent activity. It has been found that the products of the invention have significant activity against cells resistant to known anticancer agents.

The novel taxane derivatives of the formula I can be obtained within the invention by heating a derivative of the formula III (III)

wherein R, R and Ar are as defined above in a solution in an aliphatic alcohol containing 1 to 4 carbon atoms (methanol, ethanol, propanol, isopropanol) to a temperature between 20 and 97 ° C in the presence of a catalytic amount of Lewis acid such as bromide zinc. The heating time can range from 6 hours to several days.

Taxane derivatives of formula III in which R is hydrogen or acetyl may be obtained by reacting a reactive derivative of formula IV

R-O-CO-X wherein R is as defined above and X is an atom (fluoro, chloro) or -O-R or -O-CO-OR, with a baccatin III derivative

Of a 10-deacetylbaccatin of formula V (IV) halogen or

in which Ar is as defined above, G is a hydroxy-protecting group such as 2,2,2-trichloroethoxycarbonyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl or triaryl, each of which contains 1 to 4 atoms and the aryl radicals of these groups are preferably phenyl, and G ₌ acetyl or a hydroxy function such as 2,2,2-trichloroethoxycarbonyl to give the product of formula VI

(VI) in which Ar, R, are as described above by subsequently replacing the group G and optionally the hydrogen group to give the product of formula III.

and G atoms

The baccatin III or 10-deacetylbaccatin III derivative of the general formula V can be obtained by reacting a mineral or organic acid under conditions which have no effect on the protecting groups G 1 and G ₂ with a product of the general formula VII

(VII) wherein Ar 1 and G ₂ are as defined above, Boe represents a t-butoxycarbonyl group, and R ₂ and R ₃ which are the same or different, represent a hydrogen atom or a C 1 -C 4 alkyl group which is optionally substituted with one or two aryl groups (phenyl groups), or an aryl group (phenyl group) or R ₂ and R 6 together with the nitrogen atom to which they are attached form a 4- to 7-membered ring.

The product of formula VII can be obtained by reaction of an oxazolidine derivative of formula VIII

wherein Ar, R _2, R _a and Boe are as defined above, optionally in the form of an anhydride, with a taxane derivative of the formula IX

wherein G ₁ and G ₂ are as defined above, in the presence of a condensing agent and an activating agent in an organic solvent at a temperature between 0 and 90 ° C.

The oxazolidine derivative of formula (VIII) may be obtained by saponification of the corresponding ester in a basic medium and in turn reacted with a methoxyalkene optionally substituted by one or more aryl groups, gem-dimethoxyalkane optionally substituted by one or more aryl groups, or gem-dimethoxycycloalkane containing 4 to 7 atoms. carbon with a phenylisoserine derivative of the general formula X

Ar coor ₃ (X)

BocNH

OH in which Ar and Boe are as defined above and R 1 represents a C 1 -C 4 alkyl group optionally substituted by a phenyl group.

The product of formula (X) may be obtained by acylation of a beta-phenylisoserine derivative of formula (XI)

Ar COOR ₄ ) - wherein H ₂ and R 6 are as defined above.

The beta-phenylisoserine derivative of the general formula XI can be obtained by known methods and in particular from beta-phenylglycidic acid under the conditions described by J-N. Denis et al. Chem., 51, 46-50 (1986).

Derivatives of the general group of the above-mentioned meanings, of the general formula XII of the formula III, in which R represents II, in which, in turn, R__a, n may be obtained by reaction of an amine

N (CH _{7) n-NH2} / ² (XII) wherein R, _R and n are defined as above, with a taxane derivative of general formula XIII

wherein Ar and R have the meanings given above, followed by replacement of the 7-position protecting group (CL ₃ CCH ₂ OCO-) with a hydrogen atom at a temperature of less than 50 ° C.

In the following, the invention will be explained in more detail by means of specific examples thereof, the examples being illustrative only and in no way limiting the scope of the invention, which is clearly defined by the definition of the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 2.5 g of (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7-beta, 10beta-trihydroxy-9-oxo-11-taxen-13alpha-yl-3-tert, butoxycarbonylamino-2-hydroxy-3-phenylpropionate in 500 cm ^{3 of} methanol is added 0.25 g of anhydrous zinc bromide. The reaction mixture is then stirred for 50 hours at a temperature in the region of 50 ° C and subsequently cooled to a temperature in the region of 20 ° C and maintained at this temperature for 15 hours with stirring. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa) at 50 ° C. 2.5 g of a white solid foam are obtained, which is purified by chromatography on silica gel (0.063-0.2 mm, 60 g), packed into a column 2.5 cm in diameter, eluting with a dichloromethane / methanol (v / v) mixture. 98: 2 ratio and 20 cm ³ fractions were collected. Fractions 19 to 35 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. This gave 1.2 g of a white solid foam which was purified by chromatography on silica gel (0.063-0.2 mm, 60 g) packed into a 2.5 cm column using a mixture of dichloromethane and methanol as eluent. in a 99: 1 ratio. Fractions of 10 cm ³ are collected. Fractions 26 to 40 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to 40 ° C. There was thus obtained (2R, 3S) -4-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1,7alpha, 10beta-trihydroxy-9-oxo-11a-taxen-13alpha-yl-tert-butoxycarbonylamino, 0.91g. -2-hydroxy-3-phenylpropionate in the form of a white solid foam having the following characteristics:

[.alpha.] ^D @ ²⁰ = -35 DEG (c = 0.41, methanol),

D nuclear magnetic resonance spectrum:

(250 MHz, CDC1 ₃₎ δ (ppm): 1.11 (s, 3H: -CH3 I6necól7); 1.25 (s, 3H: --CH3 16xx17); 1.32 (s, 9H: -C (CH3) 3); ^1-73 (s, ^3H- CH3 19); 1.78 (s, 3H: --CH3 18); 2,15až2,45 (m, 4 H: -CF ₂ - 6 a -CH ₂ - I ^4): 2.5 (s, 3H: COCH3); 3.3 (m, 1H: --OH 2; 3.68 (ddd, 1H,

J = 12.6 and 4Hz: -H 7); 3.94 (d, 1H, J = 7Hz: --H3); 4.13 (m, 1H: --OH 10); 4.4 (b, 2H, _JAB = 9 Hz: CH _2-20); 4.64 (m, 1H: - J 2 '); 4.72 (d, 1H, J = 12Hz: --OH 7); 4.92 (dd, 1H, J = 9 and 5 Hz: --H5); 5.29 (dd, 1H, J = 10 and 2.5 Hz: --H3 '); 5.42 (d, 1H, J = 10Hz: --NECO--); 5.46 (s, 1H: --H 10); 5.75 (d, 1H, J = 7Hz: -H 2); 6.23 (t, 1H, J = 5.5 Hz: -H 13); 7.2 to 7.5 (m, 5H: -C5 H5 3 '); 7.52 [t. 2H, J = 7.5 Kz: _{--OCOC6 H5} (--H 3 and --H 5)]; 7.63 [t, 1H, J = 7.5 Hz -OCOC _{O H5} (--H 4)]; 8.14 [d, 2H, J = 7.5 Hz: _{--OCOC6 H5} (--H 2 and -H6).

The novel products of formula I have particularly interesting biological effects.

These novel products of formula I significantly inhibit abnormal cell proliferation and have therapeutic efficacy allowing the treatment of diseases in which pathologies associated with said abnormal cell proliferation occur. These pathological conditions include abnormal proliferation of malignant or non-malignant cells of various tissues and / or organs, including, without limitation, muscle, bone or binding tissues, skin, brain, lung, genital organs, lymphatic or renal system, mammary gland or blood cell, liver, gastrointestinal tract, pancreas and thyroid and adrenal glands. These pathological conditions may also include psoriasis, solid tumors, ovarian cancer, breast cancer, brain cancer, prostate cancer, colon cancer, stomach cancer, kidney cancer, ovarian cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilkin's disease, Wilms , and acute or chronic granulocyte lymphoma. The novel products of the invention are particularly useful in the treatment of ovarian cancer. The products of the invention may be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.

The products of the invention may be administered to a patient in a variety of forms appropriate to the route of administration chosen, which is preferably parenteral. Parenteral administration includes intravenous administration, intraperitoneal administration, intramuscular administration, or subcutaneous administration. More preferred administration is int11 raperitoneal administration or intravenous administration.

The invention also encompasses pharmaceutical compositions comprising at least one product of formula Ta in an amount sufficient to be used in human or veterinary medicine. These compositions can be prepared by conventional methods using one or more methods. one or more pharmaceutically acceptable excipients, carriers, or excipients. Suitable carriers include diluents, sterile aqueous media, and various non-toxic solvents. Preferably, these pharmaceutical compositions take the form of aqueous injectable solutions which contain agents, coloring agents, preservatives, or stabilizing agents.

solutions or suspensions and may contain emulsifying agents

The choice of excipients or excipients may be affected by the solubility and chemical properties of the product used, the route of administration, and conventional pharmaceutical practices.

For parenteral administration, aqueous or non-aqueous sterile solutions or suspensions are used. Natural vegetable oils such as olive oil, sesame oil or paraffin oil, or injectable organic esters, for example ethyl oleate, may be used to prepare non-aqueous solutions or suspensions. Aqueous sterile solutions may form a solution of a pharmaceutically acceptable salt dissolved in water. Aqueous solutions are suitable for intravenous administration, provided that the pH of these solutions is suitably adjusted and that isotonicity is ensured, for example, with sufficient sodium chloride or glucose. Sterilization may be accomplished by heating or other suitable means that do not adversely affect the properties of the pharmaceutical composition.

It goes without saying that all products forming part of the pharmaceutical composition must be pure and non-toxic in the amounts used.

These compositions may contain at least 0.01% of a therapeutically active agent. The amount of active ingredient in the composition is such that a suitable dosage can be prescribed.

Preferably, the pharmaceutical compositions are prepared so that the unit form contains 0.01 to 1000 mg of active ingredient in the case of parenteral administration.

The use of the products of the invention may be accomplished concomitantly with the administration of other therapeutically active agents, including antineoplastic drugs and monoclonal antibodies, as well as with immunological therapy or radiotherapy or concomitant administration of biological response modifiers. These biological response modifiers include, without limitation, lymphokines and cytokines such as intreleukins, interferons (alpha, beta or delta) and TNF. Other chemotherapeutic agents that are useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, semustine and semustine. antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs such as mercaptopurine and thioguanine, natural products such as vinea rosea alkaloids such as vinblastine, vineristine and vendesine, epidophyllotoxins, such as etoposidine, tenipididine, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbazine, adrenocore ticoid suppressors such as mititan and aminoglutethymide, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens such as diethylstilbestrol and ethynilestradiol, antioerstrogens and testosterone aspropionate as tamoxifenate.

Useful dosages within the practice of the method of the invention are those that allow for prophylactic treatment or maximal therapeutic response. Dosages vary depending on the route of administration, the particular product selected and the characteristics of the patient. Generally, these doses are those which are therapeutically effective for the treatment of disorders of the conditions.

This is due to abnormal cell proliferation. The products of the invention may be administered as often as necessary to achieve the desired therapeutic effect. For some diseases, a rapid response may be achieved to relatively high or low doses and then only low maintenance doses or no doses need to be administered. Generally, only low doses will be administered at the start of treatment, with the dose being increased as necessary until the optimal effect is achieved. For other diseases, maintenance doses of 1- to 8-times per day, preferably 1- to 4-times per day may be necessary, depending on the physiological need of the patient. It is also possible that, for some diseases, only one to two times a day will be sufficient.

In humans, these doses generally range from 0.01 to 200 mg / kg. For intraperitoneal administration, generally in the range of 0.1 to 100 mg / kg, preferably 0.5 to 50 mg / kg, and specifically 1 to 10 mg / kg. For intravenous administration, these doses are generally from 0.1 to 50 mg / kg, preferably 0.1 to 5 mg / kg, and specifically 1 to 2 mg / kg. It will be understood that the choice of the most appropriate dosage will depend on the route of administration, the weight of the patient, his general health, age and any other factors that may affect the effectiveness of the treatment.

The following example illustrates the composition of the invention.

Example 2 i

1 mg of the product obtained in Example 1 is dissolved in 1 cm @ ³ of Emulphor EI 620 ^R and 1 cm @ ^{3 of} ethanol, and subsequently recovered. The diluted solution is diluted with 18 cm ^{3 of} saline. This composition is administered by infusing saline over one hour.

Claims (5)

1. New taxane derivatives of the general formula I Ar ľ ÔK R-OCO-NH _Q (I) wherein Ar represents an aryl group, R represents a hydrogen atom or an acetyl group or a group of formula II R, (II) N- (CH3) n-NK-Cv wherein R 2 and R ₂ , which are the same or different, represent a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms or R and R ₌ , together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated or an unsaturated heterocycle which optionally contains a further heteroatom selected from the group consisting of nitrogen, optionally substituted by C 1-4 alkyl or benzyl, oxygen and sulfur, n is 2 or 3, and R represents a straight or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 8 carbon atoms 6 carbon atoms or a bicycloalkyl-containing group From 7 to 10 carbon atoms, these groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxy, C1-C4 alkyloxy, dialkylamino in which each alkyl radical contains 1 to 4 carbon atoms; carbon atoms, piperidino, morpholino, 1-piperazinyl, optionally substituted at the 4-position with C 1-4 alkyl or phenylalkyl, in which the alkyl radical contains 1 to 4 carbon atoms, cycloalkyl containing 3 C-C 6-cycloalkenyl, phenyl, cyano, carboxyl or alkoxycarbonyl in which the alkyl radical contains 1 to 4 carbon atoms, or phenyl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, a C 1 -C 4 alkyl group and a C 2 -C 4 alkyloxy group, or a saturated or unsaturated 5 or 6 membered nitrogen heterocyclyl group optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms; The cycloalkyl group, the cycloalkenyl group or the bicycloalkyl group may be optionally substituted by one or more alkyl groups having from 1 to 4 carbon atoms. Process for the preparation of a taxane derivative of the formula I according to claim 1, characterized in that the derivative of the general formula III R-OCO-NH Ar OH (III), as defined in claim 1, heats up to 97 ° C in the presence of catalytic in which Ar, R and R have a temperature in the range of 20 amounts of Lewis acid. A process according to claim 2, characterized in that the heating is carried out in an aliphatic alcohol containing 1 to 4 carbon atoms. 4. The process of claim 2 wherein the Lewis acid is zinc bromide. 5. A pharmaceutical composition comprising a sufficient amount of at least one derivative of the general formula I according to claim 1 in pure form or in combination with one or more pharmaceutically acceptable products which are inert or physiologically active.